title: Indoxyl sulfate downregulates renal expression of Klotho through production of ROS and activation of nuclear factor-ĸB.
abstract: OBJECTIVE
  Klotho, an anti-aging gene, is expressed in the kidneys, and its renal expression is decreased in chronic kidney disease (CKD). The present study aimed to examine whether renal expression of Klotho is regulated by indoxyl sulfate, a uremic toxin, using rat kidneys and human proximal tubular cells (HK-2).
  
  
  METHODS
  The effect of indoxyl sulfate on renal expression of Klotho was examined using (1) Dahl salt-resistant normotensive rats (DN), (2) Dahl salt-resistant normotensive indoxyl sulfate-administered rats (DN+IS), (3) Dahl salt-sensitive hypertensive rats (DH), and (4) Dahl salt-sensitive hypertensive indoxyl sulfate-administered rats (DH+IS). The effects of indoxyl sulfate, inhibitors of nuclear factor-κB (NF-κB) and an antioxidant on the expression of Klotho in HK-2 cells were examined.
  
  
  RESULTS
  DH+IS and DN+IS rats showed decreased expression of Klotho mRNA in the kidneys as compared with DH and DN rats, respectively. Indoxyl sulfate suppressed the expression of Klotho mRNA and protein in HK-2 cells, whereas an antioxidant, N-acetylcysteine, and NF-κB inhibitors, pyrrolidine dithiocarbamate and isohelenin, alleviated these effects.
  
  
  CONCLUSIONS
  Indoxyl sulfate downregulates Klotho expression in kidneys through production of reactive oxygen species and activation of NF-κB in proximal tubular cells. Indoxyl sulfate may be involved in reduced renal expression of Klotho in CKD.
authors.affiliation: Department of Advanced Medicine for Uremia, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Hidehisa
authors.initials: H
authors.lastname: Shimizu
authors.forename: Dilinaer
authors.initials: D
authors.lastname: Bolati
authors.forename: Ayinuer
authors.initials: A
authors.lastname: Adijiang
authors.forename: Yelixiati
authors.initials: Y
authors.lastname: Adelibieke
authors.forename: Gulinuer
authors.initials: G
authors.lastname: Muteliefu
authors.forename: Atsushi
authors.initials: A
authors.lastname: Enomoto
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Higashiyama
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Higuchi
authors.forename: Fuyuhiko
authors.initials: F
authors.lastname: Nishijima
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Niwa
mesh_terms: D000111:Acetylcysteine / Q000378:metabolism; D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D015536:Down-Regulation; D005786:Gene Expression Regulation; D005966:Glucuronidase / Q000378:metabolism*; D006801:Humans; D007200:Indican / Q000378:metabolism; D000090265:Klotho Proteins; D016328:NF-kappa B / Q000378:metabolism*; D011759:Pyrrolidines / Q000737:chemistry; D051381:Rats; D020303:Rats, Inbred Dahl; D017382:Reactive Oxygen Species; D012717:Sesquiterpenes / Q000737:chemistry; D013859:Thiocarbamates / Q000737:chemistry
chemical_list: D000975:Antioxidants; D016328:NF-kappa B; D011759:Pyrrolidines; D017382:Reactive Oxygen Species; D012717:Sesquiterpenes; D013859:Thiocarbamates; C103906:isohelenin; C020972:pyrrolidine dithiocarbamic acid; D005966:Glucuronidase; D000090265:Klotho Proteins; D007200:Indican; D000111:Acetylcysteine